US10653685B2 - Pharmaceutical compositions and methods for the treatment of hypoxia-related diseases - Google Patents

Pharmaceutical compositions and methods for the treatment of hypoxia-related diseases Download PDF

Info

Publication number
US10653685B2
US10653685B2 US15/755,262 US201615755262A US10653685B2 US 10653685 B2 US10653685 B2 US 10653685B2 US 201615755262 A US201615755262 A US 201615755262A US 10653685 B2 US10653685 B2 US 10653685B2
Authority
US
United States
Prior art keywords
hypoxia
pharmaceutical composition
tpen
alginate
administering
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
US15/755,262
Other languages
English (en)
Other versions
US20180243276A1 (en
Inventor
Jerachmiel Yori APPELBAUM
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to US15/755,262 priority Critical patent/US10653685B2/en
Publication of US20180243276A1 publication Critical patent/US20180243276A1/en
Application granted granted Critical
Publication of US10653685B2 publication Critical patent/US10653685B2/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/734—Alginic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention in some embodiments thereof, relates to pharmaceutical compositions and methods of use thereof for treating hypoxia-related diseases and, more particularly, to pharmaceutical compositions including TPEN and an alginate compound as active ingredients.
  • IRI ischemia-reperfusion injury
  • Biologically important transition-metals such as copper, iron and zinc, are also redox active metals and have been found to play a critical mediatory role in reperfusion-induced myocardial damage. Hence, their intracellular transport is tightly regulated and under normal physiological conditions, are stored in situ within protective intracellular stores proteins like ferritin and ceruloplasmin.
  • ROS reactive oxygen species
  • ROS are involved in and mediates many diseases, syndromes and pathologies, such as heart and brain stroke, brain trauma, organs transplants rejection, various neurodegenerative diseases, arthritis, etc.
  • Removing zinc by chelating agents may be an effective approach to reduce ischemic brain injury.
  • U.S. Pat. No. 5,082,851 to the present inventor teaches a metal chelating agent, N,N,N′,N′-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN), being capable of protecting heart tissue from ischemia-reperfusion damage.
  • TPEN N,N,N′,N′-tetrakis-(2-pyridylmethyl)-ethylenediamine
  • This high specificity heavy metal chelating agent is thought to work by changing the redox potential of redox-active metals (transition metals), into an inactive form before the onset of reoxygenation and hence preventing the yield and the release of hazardous reactive oxygen species (ROS).
  • ROS hazardous reactive oxygen species
  • TPEN is capable of providing heart cells up to, but not greater than, 70% protection from hypoxia stress injury.
  • the effective concentration range of TPEN was between about 1 to about 10 ⁇ M. TPEN administered at higher concentrations resulted in decreasing protection efficacy (Journal of Muscle Research and Cell Motility, October 2007, Volume 28, issues 7-8, pp. 421-428).
  • a pharmaceutical composition including TPEN or a pharmaceutically acceptable salt thereof, an alginate compound, and a pharmaceutically acceptable carrier.
  • a method of treating a hypoxia-related disease includes the step of administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition.
  • a method of treating a hypoxia-related disease includes the steps of: (i) administering to a subject in need thereof a therapeutically effective amount of TPEN or a pharmaceutically acceptable salt thereof, and (ii) administering to the subject a therapeutically effective amount of an alginate compound.
  • the alginate compound is sodium alginate.
  • the average molecular weight of the alginate compound ranges from about 10 to about 300 kDa.
  • the average molecular weight of the alginate compound ranges from about 10 to about 50 kDa.
  • the concentration of the alginate compound in the pharmaceutical composition ranges from about 0.1 to about 10% (w/v).
  • the concentration of the alginate compound in the pharmaceutical composition ranges from about 1 to about 4% (w/v).
  • the concentration of the alginate compound in the pharmaceutical composition is about 2% (w/v).
  • the concentration of the alginate compound in the pharmaceutical composition is about 1% (w/v).
  • the concentration of the TPEN in the pharmaceutical composition ranges from 0.1 to 100 ⁇ M.
  • the concentration of the TPEN in the pharmaceutical composition is about 1 to 50 ⁇ M.
  • the concentration of the TPEN in the pharmaceutical composition ranges from 1 to 10 ⁇ M.
  • the concentration of the TPEN in the pharmaceutical composition ranges from 3 to 5 ⁇ m.
  • a monomer ratio between ⁇ -L-guluronic acid and ⁇ -D-mannuronic acid in the alginate compound ranges between 1:1 and 3:1.
  • hypoxia-related disease is selected from a group consisting of cardiovascular disease, ischemic heart disease, acute myocardial infarction (AMI), ischemic brain condition, ischemic stroke, macular degeneration, ocular ischemic syndrome, ischemic optic neuropathy, diabetic retinopathy, arthritis, inflammation, sepsis, sepsis-induced shock, renal disease, tissue fibrosis, gastrointestinal disease, neurodegenerative disease, respiratory distress syndrome, bronchopulmonary displasia, pulmonary hypertension, hypoxic pulmonary hypertension, severe pulmonary hypertension, COPD, diabetic retinopathy, diabetes, corneal neovascularization, pathogenic blood vessel growth, musculoskeletal disorder, ischemic-reperfusion injury, myocardial hypoxia, or cardiac hypertrophy.
  • cardiovascular disease ischemic heart disease
  • AMI acute myocardial infarction
  • AMD acute myocardial infarction
  • ischemic brain condition ischemic stroke
  • macular degeneration ocular ischemic syndrome
  • the heart disease is an ischemic heart disease.
  • the heart disease is acute myocardial infarction.
  • the administering is effected via injection or catheterization.
  • the catheterization is intra-arterial catheterization.
  • the effective amount ranges from about 0.1 to about 10 ml.
  • the effective amount ranges from about 0.5 to about 5 ml.
  • the step of administering TPEN and the step of administering an alginate compound are effected concomitantly.
  • step of administering TPEN and the step of administering an alginate compound are effected sequentially.
  • the present invention successfully addresses the shortcomings of the presently known configurations by providing a safe and effective pharmaceutical compositions and methods of use thereof for the treatment of hypoxia-related diseases.
  • the present invention is of a pharmaceutical composition which includes as active ingredients TPEN and an alginate compound.
  • the pharmaceutical composition can be used for the treatment of hypoxia-related diseases.
  • U.S. Pat. No. 8,168,612 and U.S. patent application Ser. No. 12/530,488 teach the use of alginate compounds for the treatment of acute myocardial infarction (AMI).
  • AMI acute myocardial infarction
  • the therapeutic effect of alginate is attributed to the formation of a solid gel within the extra cellular matrix of the infarcted tissue, thereby providing mechanical support to the damaged heart tissue during its healing and repair processes following AMI.
  • alginate may exert biochemical of physiological activity that is therapeutically beneficial.
  • sodium alginate is capable of preventing hypoxia-induced injury to cultured cells. This finding was unexpected since a mechanical support could not be relevant to cultured cells and furthermore since alginate is not capable of penetrating inside living cells. Yet, as is illustrated in the Examples section hereinbelow, providing sodium alginate to cultured heart cells under hypoxia conditions resulted in substantial reduction in the amount of creatine kinase (CK) and lactate dehydrogenase (LDH) enzymes released by the cells.
  • CK creatine kinase
  • LDH lactate dehydrogenase
  • a pharmaceutical composition including N,N,N′,N′-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN) or a pharmaceutically acceptable salt thereof, an alginate compound, and a pharmaceutically acceptable carrier.
  • TPEN N,N,N′,N′-tetrakis-(2-pyridylmethyl)-ethylenediamine
  • pharmaceutical composition refers to a preparation of TPEN or a pharmaceutically acceptable salt thereof and an alginate compound as described herein with other chemical components such as pharmaceutically acceptable and suitable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of the active ingredients to a subject, or optionally to facilitate its application (contacting) in or on an inanimate object.
  • pharmaceutically acceptable carrier refers to a carrier or a diluent that does not cause significant irritation to an organism and does not inhibit the distribution, therapeutic properties or otherwise does not abrogate the biological activity and properties of the administered or applied compound.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration or application of a drug.
  • TPEN refers to the compound N,N,N′,N′-tetrakis-(2-pyridylmethyl)-ethylenediamine having the structure formula shown below.
  • TPEN is readily available from several commercial manufacturers such as, for example, Sigma Aldrich Ltd, Germany.
  • phrases “pharmaceutically acceptable salt” used herein refers to a charged species of the parent compound and its counter ion, which is typically used to modify the solubility characteristics of the parent compound and/or to reduce any significant irritation to an organism by the parent compound, while not abrogating the biological activity and properties of the administered compound.
  • pharmaceutically acceptable salts include salts comprising an anion such as a carboxylate or sulfate anion, and/or a cation such as, but not limited to, ammonium, sodium, potassium and the like. Suitable salts are described in, e.g., Birge et al. (J. Pharm. Sci. 1977, 66:1-19).
  • the final concentration of TPEN in the pharmaceutical composition ranges from about 1 to 50 ⁇ M. In another embodiment the final concentration of TPEN in the pharmaceutical composition ranges from about 0.1 to about 100 ⁇ M. In another embodiment the final concentration of TPEN in the pharmaceutical composition ranges from about 1 to about 10 ⁇ M. In another embodiment the final concentration of TPEN in the pharmaceutical composition ranges from about 3 to about 5 ⁇ M.
  • alginate compound refers to a polyanionic polysaccharide copolymer derived from sea algae (e.g., Laminaria hyperborea, L. digitata, Eclonia maxima, Macrocystis pyrifera, Lessonia nigrescens, Ascophyllum codosum, L. japonica, Durvillaea antarctica , and D. potatorum ) and which includes ⁇ -D-mannuronic (M) and ⁇ -L-guluronic acid (G) residues in varying proportions.
  • sea algae e.g., Laminaria hyperborea, L. digitata, Eclonia maxima, Macrocystis pyrifera, Lessonia nigrescens, Ascophyllum codosum, L. japonica, Durvillaea antarctica , and D. potatorum
  • M ⁇ -D-mannuronic
  • G ⁇ -L-guluronic acid
  • a suitable alginate compound can be any biocompatible, non-immunogenic and, preferably, bio-erodible alginate compound.
  • the alginate compound of the present invention has a monomer ratio between ⁇ -L-guluronic acid and ⁇ -D-mannuronic ranging between 1:1 to 3:1 and a molecular weight ranging between about 10 to about 300 kDa. In some embodiments the molecular weight of the alginate compound ranges between about 10 to about 50 kDa.
  • the alginate compound can be in a form of a free-base, an acid, a basic, an anion salt, or a monovalent cation salt.
  • the alginate compound is a soluble alginate salt such as, but not limited to, sodium alginate, potassium alginate, lithium alginate, rubidium alginate and cesium salts of alginic acid, as well as the ammonium salt, and the soluble alginates of an organic base such as mono-, di-, or tri-ethanolamine alginates, aniline alginates, and the like.
  • the alginate compound is sodium alginate.
  • Pharmaceutical grade sodium alginate which comply with all the quality and safety requirements of the European and United States of America (USA) pharmacological regulatory authorities, are readily available from several commercial manufacturers such as, for example, Novamatrix FMC Biopolymers (Drammen, Norway) or Qingdao Rongde Seaweed co., Ltd, (Qingdao, China).
  • the final concentration of the alginate compound in the pharmaceutical composition of the present invention ranges from about 0.1 to about 10% (w/v). In another embodiment the final concentration of the alginate compound in the pharmaceutical composition ranges from about 1 to about 4% (w/v). In another embodiment the final concentration of the alginate compound in the pharmaceutical composition is about 2% (w/v). In another embodiment the final concentration of the alginate compound in the pharmaceutical composition is about 1% (w/v).
  • the pharmaceutical composition of the present invention further includes at least one therapeutic agent.
  • Suitable therapeutic agents which may be included in the pharmaceutical composition of the present invention can be, for example, growth factors (e.g., basic fibroblast growth factor; bFGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), members of the TGF-family, bone morphogenic proteins (BMP), platelet-derived growth factors, angiopoietins, and other factors such as myogenic factors, transcription factors, cytokines, and homeobox gene products, polynucleotides, polypeptides, hormones, anti-inflammatory drugs, anti-apoptotic drugs or antibiotic drugs.
  • growth factors e.g., basic fibroblast growth factor; bFGF
  • VEGF vascular endothelial growth factor
  • IGF insulin-like growth factor
  • BMP bone morphogenic proteins
  • platelet-derived growth factors e.g., angiopoietins, and other factors such as my
  • the therapeutic agent or agents can be chemically linked to the alginate compound of the invention.
  • linkage can be effected via any known chemical bonding approach, preferably a covalent bond.
  • a suitable covalent bond can be, for example, an ester bond (e.g., a carboxylic ester bond, an oxyalkyl carboxylic ester bond, an amide bond, or a thioester bond), a glycosidic bond, a carbonate bond, a carbamate bond, a thiocarbamate bond, a urea bond or a thiourea bond.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredient(s) into preparations which can be used pharmaceutically.
  • Proper formulation is dependent upon the route of administration chosen.
  • the dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (see e.g., Fingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch. 1 p. 1).
  • the pharmaceutical composition may be formulated for administration in either one or more of routes depending on whether local or systemic treatment or administration is of choice, and on the area to be treated. Administration may be done orally, by inhalation, or parenterally, for example by intravenous drip or intraperitoneal, subcutaneous, intramuscular or intravenous injection, or topically (including transdermally, ophtalmically, vaginally, rectally, intranasally).
  • the pharmaceutical composition is formulated as a solution suitable for injection or parenteral administration.
  • composition of the invention is formulated for topical administration.
  • composition of the invention is formulated for ophthalmic administration.
  • composition of the invention is formulated as eye drops.
  • the amount of the pharmaceutical composition to be administered or otherwise applied will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.
  • compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA (the U.S. Food and Drug Administration) approved kit, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may, for example, comprise metal or plastic foil, such as, but not limited to a blister pack or a pressurized container (for inhalation).
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S.
  • compositions comprising active ingredient(s) according to embodiments of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of a particular medical condition, disease or disorder, as is detailed herein.
  • the pharmaceutical composition presented herein is packaged in a packaging material and identified in print, in or on the packaging material, for use in the treatment of hypoxia-related diseases.
  • the pharmaceutical composition of the present inventions can be used for protecting living cells and body tissues from hypoxia injury.
  • a method of treating a hypoxia-related disease includes a step of administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of the present invention.
  • hypoxia refers to an environment of oxygen deficiency or inadequate oxygen supply below physiological levels, such that the oxygen content (O 2 ) is less than or equal to about 5%. In most cases, hypoxic tissue will have an oxygen content that is less than or equal to about 2% or less. Hypoxia can be associated with low O 2 partial pressure (pO 2 ) less than 20 mm of mercury [mm Hg], such as less than 15 mmHg, less than 10 mm Hg, less than 5.0 mm Hg or less.
  • hypoxia-related disease refers to a disease, disorder or condition where hypoxia in a tissue of the subject is involved.
  • the hypoxia can either be a symptom or play a role in the cause, development, progression, amelioration, or cure of the disease, disorder or condition.
  • Hypoxia-related disease can be, but not limited to, a disease, disorder or condition resulting from or associated with an ischemic-reperfusion injury.
  • a hypoxia-related disease can be, but are not limited to, cardiovascular disease, ischemic heart disease, acute myocardial infarction (AMI), ischemic brain condition, ischemic stroke, macular degeneration, ocular ischemic syndrome, ischemic optic neuropathy (ION), diabetic retinopathy, arthritis, inflammation, sepsis, sepsis-induced shock, renal disease, tissue fibrosis, gastrointestinal disease, neurodegenerative disease, respiratory distress syndrome, bronchopulmonary displasia, pulmonary hypertension, hypoxic pulmonary hypertension, severe pulmonary hypertension, COPD, diabetic retinopathy, diabetes, corneal neovascularization, pathogenic blood vessel growth, musculoskeletal disorder, acute ischemic syndromes, myocardial hypoxia, cardiac hypertrophy, ischemic-reperfusion injury (IRI), IRI resulting from: cardiac heart surgery, coronary interventions (balloon and stent), arrhythmia management and organ transplantation, arrhythmias during
  • treating refers to inhibiting, preventing or arresting the development of a pathology and/or causing the reduction, remission, or regression of a pathology.
  • Those of skill in the art will understand that various methodologies and assays can be used to assess the development of a pathology, and similarly, various methodologies and assays may be used to assess the reduction, remission or regression of a pathology.
  • subject in need thereof refers to a mammalian male or female subject (e.g., human being) who is diagnosed with hypoxia-related disease. In a specific embodiment, this term encompasses individuals who are at risk to develop a hypoxia-related disease. Veterinary uses are also contemplated.
  • the subject may be of any gender or at any age including neonatal, infant, juvenile, adolescent, adult and elderly adult.
  • phrases “effective amount” used herein refers to an amount effective to provide a significant therapeutic benefit.
  • the amount of a composition to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.
  • An effective amount ranges from about 0.1 to about 10 ml (dwt between 1 and 1000 mg), preferably from about 1 to about 5 ml (dwt between 10 and 500 mg) of a concentration ranging between about 0.1 to about 10% (w/v), preferably between about 0.2 to about 5% (w/v), preferably between about 0.3 to about 2% (w/v), preferably between about 0.5 to about 1.5% (w/v), preferably about 2% (w/v), preferably about 1%.
  • terapéuticaally effective amount refers to an amount effective to provide a significant therapeutic benefit.
  • the amount of a composition to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.
  • An effective amount ranges from about 0.1 to about 10 ml (dwt between 1 and 1000 mg), preferably from about 1 to about 5 ml (dwt between 10 and 500 mg) of a concentration ranging from about 0.1 to about 10% (w/v), preferably from about 0.2 to about 5% (w/v), preferably from about 0.3 to about 2% (w/v), preferably from about 0.5 to about 1.5% (w/v), preferably about 2%, preferably about 1% (w/v).
  • the pharmaceutical composition of the present invention can be used to treat a heart infarction by providing a subject in need thereof with a therapeutically effective amount of the pharmaceutical composition of the invention in or around the infarcted myocardium.
  • the pharmaceutical composition can be administered intra-arterially, preferably intra-coronarily, via a suitable catheter such as a balloon catheter (see, for example, in Knight et al., Circulation 95:2075-2081, 1997).
  • the pharmaceutical composition of the present invention can be administered on the same day of the AMI during or after initiating reperfusion.
  • the pharmaceutical composition is administered about one day after the AMI, in about one day after the AMI, in about two days after the AMI, in about three days after the AMI, in about four days after the AMI, in about five days after the AMI, in about six days after the AMI, or in about seven days after the AMI.
  • the pharmaceutical composition of the present invention is preferably administered intra arterially via a suitable catheter.
  • the administration can be effected at the commencement, during, or following reperfusion.
  • Such a catheter will typically comprise an elongated flexible catheter body containing one or more interior passageways (lumens), a proximal portion which allows material to be introduced into the catheter body and to flow through the lumen, a distal portion optionally having a tapered end and one or more exit ports at or near the end of the distal portion to permit material to exit the catheter in response to applied pressure.
  • a proximal portion which allows material to be introduced into the catheter body and to flow through the lumen
  • a distal portion optionally having a tapered end and one or more exit ports at or near the end of the distal portion to permit material to exit the catheter in response to applied pressure.
  • the ischemia-causing thrombus Prior to or concomitantly with the injection of the pharmaceutical composition of the present invention, the ischemia-causing thrombus must be cleared via, for example, thrombolysis, mechanical recanalization or embolectomy.
  • Thrombolysis involves intravenously or intra-arterially administering plasminogen activators such as t-PA.
  • Intra-arterial thrombolysis involves direct catheterization of an occluded artery and local administration of the thrombolytic agent via the catheter using procedures known in the art such as described, for example, in US Patent Publication No. 20080095760, Furlan et al. (JAMA 282:2003-11, 1999), Arnold et al. (J Neurol Neurosurg Psych 75:857-62, 2004) and Lindsberg and Mattle (Stroke 37:922-8, 2006).
  • Delivering the pharmaceutical composition of the present invention to a precise desired location in cerebral artery, such as the site of occlusion causing the stroke, may be effected using procedures known in the art such are described, for example, in U.S. Pat. Nos. 4,995,862, 6,379,373 and U.S. Pat. Appl. Publication No. 20050228359.
  • the pharmaceutical composition of the present invention and a catheter suitable for administering thereof into a predetermined location within a cerebral artery may, if desired, be included in a kit which further comprises a packaging material identifying the pharmaceutical composition for use in the treatment of an ischemic brain condition.
  • the pharmaceutical composition of the present invention can also be used to treat diseases and conditions associated with an ischemic muscle tissue, such as an ischemic striated muscle tissue, by providing the ischemic muscle tissue with a therapeutically effective amount of the pharmaceutical composition.
  • an ischemic muscle tissue such as an ischemic striated muscle tissue
  • the pharmaceutical composition of the present invention can also be used for protecting and preserving an extracorporeal tissue or organ from ischemia and oxygen radical-related damage, by immersing or bathing the extracorporeal tissue or organ or cell in an effective amount of the pharmaceutical composition.
  • the hypoxia-related disease can be treated by the steps of: (a) administering to a subject in need thereof a therapeutically effective amount of TPEN or a pharmaceutically acceptable salt thereof; and (b) administering to the subject a therapeutically effective amount of an alginate compound.
  • steps (a) and (b) are effected concomitantly.
  • steps (a) and (b) are effected sequentially.
  • compositions, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
  • a compound or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range.
  • the phrases “ranging/ranges between” a first indicate number and a second indicate number and “ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • TPEN N,N,N′,N′-tetrakis-(2-pyridylmethyl)-ethylenediamine
  • Sprague Dawley rat hearts (1-2 days old) were sterilely removed and bathed three times in Ca ++ and Mg ++ —free PBS to remove excess blood cells.
  • the hearts were minced to small fragments and then agitated in a proteolytic enzyme-RDB solution (Life Science research, Inst., Nes Ziona, Israel) prepared from a fig tree extract as described previously (Brik et al., Basic Res. Cardiol. 85:237-246, 1990), Shneyvays et al., J Mol Cell Cardiol. 33:1249-1261, 2001).
  • the RDB-solution was then diluted 1:200 in PBS at 25° C. for a few cycles of 10 min each.
  • the supernatant suspension containing dissociated cells to which medium containing 10% horse serum was added, was centrifuged at 500 g for 5 min. After centrifugation, the supernatant phase was discarded, and cells were re-suspended in Dulbecco's modified Eagle medium supplemented with 10% heat-inactivated horse serum and 0.5% chick embryo extract.
  • Cell suspensions were diluted to 1 ⁇ 10 6 cells/ml, and 300 pl samples were placed in 24 well plates (4 plates) collagen/gelatin coated plastic culture dishes. A confluent monolayer, which exhibits spontaneous contractions in each well, developed in the culture within 2 days.
  • cardiomyocytes/well from neonatal rat hearts were cultured with glucose-free PBS and exposed to hypoxia (oxygen and glucose deprivation) for 180 min. using a procedure essentially as described by O. Golan et al. (Biochemical pharmacology, 81 (2011), pp. 1219-1227)
  • hypoxia was performed in a closed chamber by replacement of air with 100% Argon.
  • Oxygen levels in the N 2 atmosphere was below 1%.
  • the pO2 in the PBS was ⁇ 0.4 Torr.
  • Hypoxic stress injury was determined based on the activity of lactate dehydrogenase (LDH) and creatine kinase (CK) released from the cells, at the end of 3 hr. hypoxic phase, and consequently after additional 2 hr. of reoxygenation.
  • LDH lactate dehydrogenase
  • CK creatine kinase
  • CK activity was determined within the cardiac cell medium (PBS) using CK-NAC Reagent (Creatine kinase, activated by N-acetyl cysteine) from Thermo Fisher Scientific Inc. Middletown, Va. 22645-1905 USA.
  • PBS cardiac cell medium
  • CK-NAC Reagent Creatine kinase, activated by N-acetyl cysteine
  • Lactate dehydrogenase activity was determined within the cardiac cell medium (PBS) using LDH-L kit (Thermo Trace, Melbourne, Australia). Medium (PBS) samples (25 pl) were collected at the end of the hypoxic insult (after 180 min).
  • Tables 1-10 hereinbelow show that TPEN combined with sodium alginate effectively protected cultured heart cells from hypoxia injury.
  • CK reduction is an indication that sodium alginate is capable of protecting cultured heart cells from hypoxia injury. This observation was highly surprising since the alginate molecule having a molecular weight of 20-50 kDa was not expected to be able to penetrate into the cultured cells or to interact therein.
  • CK and LDH released from cells For example, sodium alginate provided at concentrations of 0.1 and 0.3%, (combined with 3 ⁇ M TPEN) resulted in 65.5 and 74.3% CK reduction, respectively (Tables 2-3). Similarly, administering sodium alginate alone (without TPEN), at concentrations of 0.1 and 0.3%, resulted in CK reduction of 8.7 and 64.5%, respectively, and LDH reduction of 13.8 and 28.7%, respectively (Tables 7-9).
  • TPEN Administering TPEN at increasing concentrations from 0.3 to 3 ⁇ M resulted in respective reductions of CK and LDH released from the cells.
  • Table 2 the TPEN effect on CK and LDH reduction was declining when TPEN was administered at above-optimal concentrations.
  • TPEN administered at 7.5 ⁇ M resulted in CK reduction of just 46.2%, compared with a 65.5% CK reduction resulted from administering TPEN at a concentration of 3 ⁇ M (combined with 0.1% sodium alginate; Table 2).
  • TPEN administered at a concentration of 7.5 ⁇ M, combined with sodium alginate at a concentration of 0.3% resulted in 71.2% CK reduction (Table 3).
  • **Values are calculated as follows: [(measured CK activity in treated cell culture) ⁇ (measured CK activity in untreated cell culture)]/[(measured CK activity in untreated cell culture) ⁇ ([(measured CK activity in control cell culture not exposed to hypoxia)] ⁇ 100.
  • **Values are calculated as follows: [(measured CK activity in treated cell culture) ⁇ (measured CK activity in untreated cell culture)]/[(measured CK activity in untreated cell culture) ⁇ ([(measured CK activity in control cell culture not exposed to hypoxia)] ⁇ 100.
  • **Values are calculated as follows: [(measured CK activity in treated cell culture) ⁇ (measured CK activity in untreated cell culture)]/[(measured CK activity in untreated cell culture) ⁇ ([(measured CK activity in control cell culture not exposed to hypoxia)] ⁇ 100.
  • **Values are calculated as follows: [(measured LDH activity in treated cell culture) ⁇ (measured LDH activity in untreated cell culture)]/[(measured LDH activity in untreated cell culture) ⁇ ([(measured LDH activity in control cell culture not exposed to hypoxia)] ⁇ 100.
  • **Values are calculated as follows: [(measured LDH activity in treated cell culture) ⁇ (measured LDH activity in untreated cell culture)]/[(measured LDH activity in untreated cell culture) ⁇ ([(measured LDH activity in control cell culture not exposed to hypoxia)] ⁇ 100.
  • **Values are calculated as follows: [(measured LDH activity in treated cell culture) ⁇ (measured LDH activity in untreated cell culture)]/[(measured LDH activity in untreated cell culture) ⁇ ([(measured LDH activity in control cell culture not exposed to hypoxia)] ⁇ 100.
  • **Values are calculated as follows: [(measured CK activity in treated cell culture) ⁇ (measured CK activity in untreated cell culture)]/[(measured CK activity in untreated cell culture) ⁇ ([(measured CK activity in control cell culture not exposed to hypoxia)] ⁇ 100.
  • **Values are calculated as follows: [(measured CK activity in treated cell culture) ⁇ (measured CK activity in untreated cell culture)]/[(measured CK activity in untreated cell culture) ⁇ ([(measured CK activity in control cell culture not exposed to hypoxia)] ⁇ 100.
  • **Values are calculated as follows: [(measured LDH activity in treated cell culture) ⁇ (measured LDH activity in untreated cell culture)]/[(measured LDH activity in untreated cell culture) ⁇ ([(measured LDH activity in control cell culture not exposed to hypoxia)] ⁇ 100.
  • **Values are calculated as follows: [(measured LDH activity in treated cell culture) ⁇ (measured LDH activity in untreated cell culture)]/[(measured LDH activity in untreated cell culture) ⁇ ([(measured LDH activity in control cell culture not exposed to hypoxia)] ⁇ 100.
  • test compositions are: saline (negative control) and a TPEN/Alginate solution composed of 3 ⁇ M TPEN and 1% (w/v) sodium alginate (UP-VLVG, Mw 20-50 kDa) in saline.
  • AMI Acute Myocardial Infarction
  • the guiding catheter and positioned in the Left Main coronary artery and the wire, advanced under fluoroscopic guidance, is positioned in the distal Circumflex coronary artery.
  • the balloon catheter is advanced into the coronary artery over the wire and positioned proximal to the first marginal branch.
  • the animals are anti-coagulated with 750-1000 USP units of intravenous sodium heparin.
  • the PTCA balloon is inflated to occlude the coronary artery.
  • Complete occlusion of the coronary artery is confirmed by ST-segment elevation on the electrocardiogram and near absence of LV posterior wall motion assessed by transthoracic 2-dimensional echocardiography. In all instances, the coronary occlusion is maintained for 3 to 5 hours.
  • the balloon is deflated to allow for coronary reperfusion.
  • test solution (2 ml volume) is injected into the animals' Circumflex coronary artery.
  • the coronary injection of the test solution is made either on the same day of the AMI (about one hour following initiating reperfusion), or 2-5 days following the AMI. Dogs are randomly assigned to receive any of the test solution. All animals are followed for 4 months following the AMI. Angiographic and echocardiographic measurements are made at baseline, prior to inducing the AMI, just prior to administering the test solutions and at two and four months thereafter.
  • LV end-systolic (ESV) and ESV) volumes are calculated from LV silhouettes using the area-length method (Dodge et al., Am J Cardiol. 1966; 18:10-24, 1966).
  • Left ventricular EF is calculated as the ratio of the difference of EDV and ESV to EDV times 100 (Sabbah et al., Circulation 89:2852-2859, 1994).
  • Percent systolic wall thickening of the LV anterior wall, posterior wall and inter-ventricular septum are also measured using the short axis view and each calculated as the ratio of wall thickness at end-diastole to wall thickness at end-systole divided by wall thickness at end-diastole times 100. Extrasystolic and post-extrasystolic beats are excluded from all analysis.
  • angiographic and echocardiographic data are analyzed using repeated measures analysis of variance (ANOVA) with alpha set at 0.05. If the overall ANOVA is significant, then pairwise comparisons between pre-treatment (PRE) and 2 and 4 months are performed using the Student-Newman-Keuls test. For this test a p-value lower than 0.05 is considered significant.
  • ANOVA repeated measures analysis of variance
  • ⁇ the change in each measure from PRE to 2 months and PRE to 4 months post-treatment is calculated for each of the two study arms.
  • a t-statistic for two means is used with p ⁇ 0.05 considered significant.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
US15/755,262 2015-08-24 2016-09-13 Pharmaceutical compositions and methods for the treatment of hypoxia-related diseases Active US10653685B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US15/755,262 US10653685B2 (en) 2015-08-24 2016-09-13 Pharmaceutical compositions and methods for the treatment of hypoxia-related diseases

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201562208914P 2015-08-24 2015-08-24
US15/755,262 US10653685B2 (en) 2015-08-24 2016-09-13 Pharmaceutical compositions and methods for the treatment of hypoxia-related diseases
PCT/US2016/051482 WO2017035542A1 (en) 2015-08-24 2016-09-13 Pharmaceutical compositions and methods for the treatment of hypoxia-related diseases

Publications (2)

Publication Number Publication Date
US20180243276A1 US20180243276A1 (en) 2018-08-30
US10653685B2 true US10653685B2 (en) 2020-05-19

Family

ID=58101120

Family Applications (1)

Application Number Title Priority Date Filing Date
US15/755,262 Active US10653685B2 (en) 2015-08-24 2016-09-13 Pharmaceutical compositions and methods for the treatment of hypoxia-related diseases

Country Status (8)

Country Link
US (1) US10653685B2 (ja)
EP (1) EP3340985B1 (ja)
JP (1) JP6849683B2 (ja)
CN (1) CN108076628A (ja)
AU (1) AU2016311504A1 (ja)
CA (1) CA2996614C (ja)
IL (1) IL257689B (ja)
WO (1) WO2017035542A1 (ja)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022246503A1 (en) * 2021-05-24 2022-12-01 The Florey Institute Of Neuroscience And Mental Health Methods for mediating vasoconstriction

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5082851A (en) * 1989-02-20 1992-01-21 Hadassah Medical Organization Pharmaceutical composition for protecting the heart comprising a heterocyclic ethylenediamine derivative and methods for the use thereof
WO2004098669A1 (en) 2003-05-05 2004-11-18 Ben-Gurion University Of The Negev Research And Development Authority Injectable cross-linked polymeric preparations and uses thereof
US20070027064A1 (en) * 2003-03-27 2007-02-01 Appelbaum Jerachmiel Yori Pharmaceutical compositions for inhibiting metal ion dependent enzymatic activity and methods for the use thereof
US20100216739A1 (en) * 2007-03-13 2010-08-26 Biolinerx Ltd Method of promoting muscle tissue repair
US20120276152A1 (en) * 2011-04-29 2012-11-01 Syed Hossainy Systems and methods of using zinc-chelator to treat myocardial infarction
WO2013003445A1 (en) 2011-06-30 2013-01-03 Athena Cardionet Ltd. Tetra-pyridine compounds and composition for protecting cells, tissues and organs against ischemia-reperfusion injury

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5082851A (en) * 1989-02-20 1992-01-21 Hadassah Medical Organization Pharmaceutical composition for protecting the heart comprising a heterocyclic ethylenediamine derivative and methods for the use thereof
US20070027064A1 (en) * 2003-03-27 2007-02-01 Appelbaum Jerachmiel Yori Pharmaceutical compositions for inhibiting metal ion dependent enzymatic activity and methods for the use thereof
WO2004098669A1 (en) 2003-05-05 2004-11-18 Ben-Gurion University Of The Negev Research And Development Authority Injectable cross-linked polymeric preparations and uses thereof
US20100216739A1 (en) * 2007-03-13 2010-08-26 Biolinerx Ltd Method of promoting muscle tissue repair
EP2136783B1 (en) 2007-03-13 2013-04-24 Biolinerx Ltd. A method of promoting muscle tissue repair
US20120276152A1 (en) * 2011-04-29 2012-11-01 Syed Hossainy Systems and methods of using zinc-chelator to treat myocardial infarction
WO2013003445A1 (en) 2011-06-30 2013-01-03 Athena Cardionet Ltd. Tetra-pyridine compounds and composition for protecting cells, tissues and organs against ischemia-reperfusion injury

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
"Prevention" in Glossary of medical education terms: Parts 1-7. Wojtczak, A., Ed. Medical Teacher. vol. 24, Nos. 2-6 and vol. 25, No. 1&2. 2002. (Year: 2002). *
Aksnes et al., Mechanism for mycardial potassium uptake after short-lasting myocardial ischemia, Experimental Medial Research, S.29:33 (Abstract).
Appelbaum et al., Role of nitric oxide and TPEN, a potent metal chelator, in ischaemic and reperfused rat isolated hearts, Clin Exp Pharmacol Physiol 25: 496-502, 1998. (Abstract).
Appelbaum et al., Tpen, a heavy metal chelator, protect the isolated perfused rat heart from reperfusion-induced arrhythmias, Journal of Molecular and Cellular Cardiology. Aug. 1988. (Abstract).
Appelbaum et al., TPEN, a transition metal chelator, improves myocardial protection during prolonged ischemia, J Heart Lung Transplant.;11(5):979-85. Sep.-Oct. 1992. (Abstract).
Frey et al., Intracoronary Delivery of Injectable Bioabsorbable Scaffold (IK-5001) to Treat Left Ventricular Remodeling After ST-Elevation Myocardial Infarction, Cir Cardiovascular Interventions 7:806-812 (2014).
IK-5001 for the prevention of remodeling of the ventricle and congestive heart failure after acute myocardial infarction (PRESERVATION-1), donwloaded Jun. 27, 2019, from clinicaltrials.gov/ct2/show/NCT01226563?term=ik&rank=3.
Lian et al., Mars, a novel preservation solution is superior to uw solution in rat cardiac and kidney transplantation models, London, ON,Canada. The Journal of Urology vol. 181, No. 4, Supplement, Apr. 29, 2009.
Shmist et al., N,N,N′,N′-Tetrakis(2-pyridylmethyl)-ethylenediamine Improves Myocardial Protection against Ischemia by Modulation of Intracellular Ca2+ Homeostasis, Journal of Pharmacology and Experimental Therapeutics. June, 313(3):1046-1057 (2005).
Shmist et al., TPEN Improves Myocardial Protection against Ischemia by Modulation of Intracellular Ca2+ Homeostasis, American Society for Pharmacology and Experimental Therapeutics, pp. 1-39 (2005) (Downloaded from jpet.aspetjournals.org at ASPET Journals on Mar. 29, 2019).
SodiumAlginate (Excipient-pharmacologicaly inactive ingredient) downloaded Jun. 26, 2019, from drugs.com/inactive/sodium-alginate-268.html.
SodiumAlginate (Excipient—pharmacologicaly inactive ingredient) downloaded Jun. 26, 2019, from drugs.com/inactive/sodium-alginate-268.html.
Sztretye et al., Effect of TPEN on the calcium release of cultured C2C12 mouse myotubes, J Muscle Res Cell Motil, 28:421-428 (2007).
Wilkinson, G. Pharmacokinetics, The Dynamics of Drug Absorption, Distribution, and Elimination (2001). In: Goodman and Gilman's the pharmacological basis of therapeutics. International edition, 10th edition, Mc Grow Hill, 971. (Year: 2001). *
Yamada et al., Is reperfusion-induced ventricular fibrillation an oxygen-dependent or a flow-dependent phenomenon?, J Mol Cell Cardiol, 20(Supplement V):31 (1998) (Abstract).

Also Published As

Publication number Publication date
JP2018527407A (ja) 2018-09-20
AU2016311504A1 (en) 2018-03-08
WO2017035542A1 (en) 2017-03-02
JP6849683B2 (ja) 2021-03-24
US20180243276A1 (en) 2018-08-30
CA2996614A1 (en) 2017-03-02
IL257689B (en) 2021-03-25
IL257689A (en) 2018-04-30
EP3340985A1 (en) 2018-07-04
EP3340985B1 (en) 2020-11-25
CN108076628A (zh) 2018-05-25
CA2996614C (en) 2023-12-12
EP3340985A4 (en) 2019-04-10

Similar Documents

Publication Publication Date Title
US10702556B2 (en) Compositions and methods for inducing angiogenesis
CN106535920B (zh) Ang-(1-7)衍生物寡肽及其使用和生产方法
CN104138377A (zh) 一种治疗重症高原病的药物组合物
KR20190080875A (ko) 모발 성장 자극을 위한 알파-케토부티레이트, 알파-케토글루타레이트, 및 2-하이드록시부티레이트
EP3154551B1 (en) The use of dextran sulfate having an average molecular weight below 10000 da for inducing angiogenisis in a subject
EP2837390A1 (en) Combined Pharmaceutical Preparation for Use in Treating Neuromuscular Disorders
KR102182513B1 (ko) 인간 유래 심장 줄기세포 미세구의 제조 방법 및 용도
US9504730B2 (en) Method of achieving a thymosin beta 4 concentration in a human patient
CN117338762A (zh) 曲恩汀将铜递送到缺血组织的用途
US10653685B2 (en) Pharmaceutical compositions and methods for the treatment of hypoxia-related diseases
US20170027977A1 (en) Methods useful in the prevention of hypoxic injury
TW201402136A (zh) 含有海藻糖之預防肺栓塞用哺乳動物細胞懸浮液
US20130281472A1 (en) Composition and method for treating or preventing skeletal muscle fibrosis
WO2016110225A1 (zh) 一种磺酰胺类药物组合物
CN116270715A (zh) Otud5在制备防治心肌缺血再灌注损伤药物中的应用
US10702524B2 (en) Use of a compound in repairing nerve injury
WO2020021545A1 (en) Cannabidiol and glucosamine for treating inflammatory joint diseases
US20180021275A1 (en) Method of treating idiopathic pulmonary fibrosis
US20230381186A1 (en) Compounds and Methods for Treating or Preventing Anterior Segment Ocular Disorders and/or Retinal Degenerations
JP2007512319A (ja) 心臓血管障害及び疾患を治療するための組成物及び方法
WO2016161462A1 (en) Ischemic tolerant mesenchymal stem cells and their factors in the treatment of cardiovascular conditions
CN111214465A (zh) 维拉帕米的抗衰老用途
WO2016074203A1 (zh) 包含二氧化氯的细胞凋亡诱导剂及其在制备化妆品或抗衰老或抗肿瘤药物中的用途
KR20230172252A (ko) 기능강화 줄기세포를 포함하는 관절염 예방 또는 치료용 조성물
US20180110833A1 (en) Nerve growth factor composition and powder injection

Legal Events

Date Code Title Description
FEPP Fee payment procedure

Free format text: ENTITY STATUS SET TO UNDISCOUNTED (ORIGINAL EVENT CODE: BIG.); ENTITY STATUS OF PATENT OWNER: MICROENTITY

FEPP Fee payment procedure

Free format text: ENTITY STATUS SET TO SMALL (ORIGINAL EVENT CODE: SMAL); ENTITY STATUS OF PATENT OWNER: MICROENTITY

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: FINAL REJECTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE AFTER FINAL ACTION FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: NOTICE OF ALLOWANCE MAILED -- APPLICATION RECEIVED IN OFFICE OF PUBLICATIONS

STPP Information on status: patent application and granting procedure in general

Free format text: AWAITING TC RESP., ISSUE FEE NOT PAID

FEPP Fee payment procedure

Free format text: ENTITY STATUS SET TO MICRO (ORIGINAL EVENT CODE: MICR); ENTITY STATUS OF PATENT OWNER: MICROENTITY

STPP Information on status: patent application and granting procedure in general

Free format text: PUBLICATIONS -- ISSUE FEE PAYMENT VERIFIED

STCF Information on status: patent grant

Free format text: PATENTED CASE

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: MICROENTITY

FEPP Fee payment procedure

Free format text: SURCHARGE FOR LATE PAYMENT, MICRO ENTITY (ORIGINAL EVENT CODE: M3554); ENTITY STATUS OF PATENT OWNER: MICROENTITY

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YEAR, MICRO ENTITY (ORIGINAL EVENT CODE: M3551); ENTITY STATUS OF PATENT OWNER: MICROENTITY

Year of fee payment: 4